Final Flashcards
what is coronary heart disease
occurs when coronary blood circulation fails to adequately supply the heart with blood
primarily caused by athlerosclerosis
risk of developing CHD is directly proportional to the levels of choleserol in the blood
CHD causes 1/3 of deaths in Canada
where is cholesterol synthesized
the liver
structure of lipoproteins
outer hydrophilic shell made of phospholipids
core is made of lipophilic cholesterol and TGs
have apolipoproteins embedded in the phospholipid shell
used to transport cholesterol and TGs in the blood
apolipiproteins
allow recognition of lipoproteins by cells
activate enzymes that metabolize lipoproteins
increase structural stability of lipoproteins
apolipoprotein A-I
non-hepatic tissue back to the liver
HDL
apolipoprotein B-100
liver to non-hepatic tissues
VLDL
LDL
is protein or lipid more dense
protein
VLDL
TGs from liver to adipose and muscle
TG-rich core and account for almost all TGs in the blood
some studies suggest that high VLDL contributes to athlerosclerosis
contain one apo B-100
LDL
cholesterol to non-hepatic tissue
cholesterol-rich core
one apo B-100
clear link between LDL cholesterol and development of athlerosclerosis, reducing LDL halts or even reverses it
“bad cholesterol”
HDL
cholesterol from non-hepatic tissue back to the liver
promote cholesterol removal from the blood
cholesterol is main core lipid
elevated HDL decreases the risk of CHD, protects against athlerosclerosis
A-I, A-II, A-IV
A-I mediates the beneficial effects
“good cholesterol”
athlerosclerosis
LDL initiates by moving into the sub-endothelial space of the arterial epithelium
LDL becomes oxidized
oxidation of LDL causes recruitment of monocytes, which are converted to macrophages
macrophages ingest oxidized LDL, become large and vacuolated, called foam cells
foam cells accumulate below the epithelium, a fatty streak appears
then platelets adhere, smooth muscle migrates and collagen synthesis occurs, forming a fibrous cap
end result is an athlerosclerotic lesion with lipid core and tough fibrous cap
cap can rupture and a thrombus can form and partially or completely block blood flow
what kind of process is athlerosclerosis
inflammatory
what does LDL do in atherosclerosis?
causes mild injury to the arterial endothelium
cholesterol screening
males over 40
females over 50 or post-menopausal
also diabetes heart disease or family history of it hypertension central obesity smoke or recently stopped inflammatory or renal disease
how is cardiovascular risk assessed?
Framingham Risk Score gender age total blood cholesterol smoking status HDL systolic blood pressure
gives 10 year risk
may underestimate youth, women and ppl with metabolic syndrome
metabolic syndrome
3 or more of: central obesity elevated TGs low HDL hyperglycemia hypertension
gives increased risk for CHD and type 2 DM
1 in 4 canadians
non-drug treatment for LDL
first line treatment is lifestyle
diet - less cholesterol and saturated fats, more fiber, plant sterols and stanols
weight control - weight loss lowers LDL and reduces risk of CHD
exercise - CV exercise decreases LDL, insulin resistance, blood pressure and increases HDL
smoking - smoking decreases HDL and increases LDL so should quit (especially important risk factor in ppl under 50)
when is drug treatment given for LDL
when targets arent reached through lifestyle intervention
what are the classes of drugs used to treat elevated blood lipids
statins bile acid sequestrants nicotinic acid cholesterol absorption inhibitors fibric acid derivatives (fibrates)
cholesterol synthesis
mevalonic acid pathway
acetyl-CoA (citric acid cycle) is converted to 3-OH-3-methylglutaryl CoA (HMG CoA)
HMG CoA is converted to mevalonic acid by HMG CoA reductase rate limiting step
eventually get cholesterol
synthesis is greatest during the night
how do statins work
they inhibit HMG CoA reductase, the rate limiting step of cholesterol synthesis
causes an upregulation of hepatic LDL receptors, so the liver removes more cholesterol from the blood
net effect is decrease in blood LDL levels, increase in HDL and decrease in TGs
are effective in both primary and secondary prevention
primary vs secondary prevention
primary = preventing development of disease
secondary = preventing recurrence
highest prescribed statins
atorvastatin (lipitor) is highest prescribed drug in Canada
rosuvastatin (crestor) is 4th highest in canada
atorvastatin
low oral bioavailability
large fraction of absorbed dose is extracted by the liver (site of action)
distributes primarily to liver, but also spleen, adrenal glands and skeletal muscle
metabolized by CYP3A4
predominantly eliminated in the feces, minimal renal excretion
rosuvastatin
low oral bioavailability
large fraction extracted by liver (site of action)
distributes mostly to liver, some to skeletal muscle
not extensively metabolized
eliminated mostly in feces, minimal renal
plasma concentrations are 2 times higher in asian patients compared to caucasians, so initial dose should be lower
adverse effects of statins
in general well tolerated
most common adverse effect is myopathy (muscle injury) - get muscle aches and weakness
rhabodomyolysis is rare but more serious - muscle lysis with severe pain, diagnosed by measuring blood levels of creatine kinase, also get hyperkalemia and may get acute kidney failure…treat with IV fluids to preserve kidney function
low incidence of hepatotoxicity - do liver function tests before and throughout
potentially teratogenic bc cholesterol is needed for cell membranes etc
nicotinic acid
niacin
LDL drug
inhibits hepatic secretion of VLDL and therefore decreases TGs in the blood
since LDL is a by-product of VLDL it also decreases LDL
increases HDL
side effects of niacin
intense facial flushing heptotoxicity hyperglycemia skin rash increase in uric acid levels
bile acids
negatively charged
produced in the liver from cholesterol
secreted into intestine for absorption of dietary fats and fat soluble vitamins
undergo entero-hepatic recycling (95% reabsorbed)
bile acid sequestrants
large and positively charged
attract and bind bile acids so they can’t be reabsorbed
causes an increased demand for bile acid synthesis which requires LDL
increase hepatic LDL receptors and increase uptake
get decreased plasma LDL
adverse effects of bile acid sequestrants
not absorbed so no systemic side effects
GI tract, ie constipation and bloating
bind negatively charged molecules so decrease the absorption of some drugs including thiazide diuretics, digoxin, warfarin, some antibiotics
NPC1L1
transporter that is responsible for intestinal uptake of the majority of dietary cholesterol
cholesterol absorption inhibitors
only one is ezetimibe (Zetia)
inhibits NPC1L1
decreases intestional cholesterol absorption and lowers LDL, however there can be a compensatory increase in hepatic cholesterol synthesis therefore often prescribed in combination with statin
vytorin
a new pill that contain simvastatin with ezetimibe
fibric acid derivatives
fibrates
most effective for lowering TGs
increase HDL, no effect on LDL though
bind to and activate PPARalpha (nuclear receptor)
1) increases synthesis of LPL to enhance clearance of TG-rich lipoproteins
2) decreases apolipoprotein C-III production, which allows for increases LPL activity
3) increases A-I and A-II levels (this is how it increases HDL)
adverse effects of fibrates
increased risk of gallstones
myopathy (need tone especially careful if using with statin, give low dose of statin and monitor)
hepatoxicity
hypertension definition
elevated systemic arterial blood pressure
blood pressure
the force against the walls of your arteries as blood is pumped through your body
measured with a sphygmomanometer
what should be done to accurately measure BP
sit for at least 5 min
no caffeine or nicotine within 30 in
feet touching the ground
arms elevated to heart level
two measurements in each arm 5 min apart
before diagnosing hypertension repeat 3 time at least 2 weeks apart
systole
when the heart contracts
diastole
period of time when the heart fills after contracting
normal BP
sys <120 AND dia <80
prehypertension BP
sys 120-139
OR
dia 80-89
stage 1 hypertension BP
sys 140-159
OR
90-99
stage 2 hypertension BP
sys >160
OR
dia >100
primary hypertension
no known cause
most cases
secondary hypertension
identifiable cause
fewer cases
causes of secondary hypertension
kidney disease hyperthyroidism pregnancy erthropoetin pheochromocytoma (tumor on adrenal gland that release a lot of epinephrine) sleep apnea contraceptive use
factors that influence blood pressure
amount of water and salt in your body
condition of kidneys, nervous system and blood vessels
levels of certain hormones in the body
risk factors for hypertension
obesity stress smoking high salt diet diabetes African NSAIDs oral contraceptives pseudoephedrine
consequences of hypertension
myocardial infarction
kidney failure
stroke
renal damage
do you get symptoms as soon as you have hypertension
no is a “silent killer”
cardiac output
determined by heart rate, heart contractility, blood volume and venous return
increase in any = increase in blood pressure (bc CO increases)
peripheral resistance
determined by arteriolar constriction
constriction = rise in BP
what determines BP
cardiac output x peripheral resistance
what 3 body systems regulate BP?
sympathetic nervous system
renin-angiotensin-aldosterone system
renal regulation of BP
how does SNS regulate BP
through the baroreceptor reflex that keeps BP at a set level
baroreceptors in aortic arch and carotid sinus sense BP and send signal to brain
if too low brainstem sends impulses along SNS neurons to stimulate heart to increase cardiac output and to smooth muscle of arteries to constrict
if too high sympathetic activity is decreased = decreased CO and vasodilation
responds rapidly ie seconds or minutes
how does the activity of baroreceptors oppose drug therapy for BP
set point in patients with hypertension is high so tries to get back to that point
what does the RAAS system regulate and what organ does it target
BP, blood volume and electrolyte balance
targets kidney and vascular smooth muscle
timing of RAAS
hours or days
RAAS how it works
when there is decrease in blood volume, blood pressure or stimulate on beta 1 receptors of juxtaglomerular cells renin is released
renin is synthesized and released by juxtaglomerular cells of the kidney (into the blood)
it catalyzes the rate-limiting step, converts angiotensinogen to angiotensin I
angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II
angiotensin II is a potent vasoconstrictor by binding to AT1 receptors
angiotensin II stimulates aldosterone release from adrenal cortex which acts on kidneys to increase sodium retention and therefore water retention also
angiotensin II acts on the posterior pituitary to release ADH which also causes water retention in the kidneys
so overall get vasoconstriction = increased PR, salt and water retention = increased blood volume and CO
have increased BP
renal regulation of blood pressure
if BP is decreased for a long time the kidney retains water
get increased blood volume
causes increased CO and therefore BP
non-drug treatment for hypertension
if dia 90-95 or in combination with drug therapy
decreasing body weight restricting sodium intake exercise potassium supplementation DASH diet stopping smoking alcohol restriction
how does obesity cause hypertension
direct relationship between obesity and hypertension
obese have increased insulin which causes tubular reabsorption of Na and therefore water = higher blood volume
obese also have increase SNS activity
how does exercising help hypertension
regular exercise decreases extracellular fluid volume (i.e. blood volume) and circulating levels of catecholamines
potassium supplementation and hypertension
total body K levels are inversely correlated with BP
high K = lower BP
high K diets decrease BP by increasing sodium excretion, decreasing renin release and causing vasodilation
found in fresh fruits and vegetables
no high K diet for ppl on ACEIs
DASH diet
dietary approaches to stop hypertension
best results seen in ppl with prehypertension
eat lots of fruits, veggies, low fat dairy, lean meat. whole grains, nuts and legumes
cut out saturated fats, fats overall and cholesterol
smoking and hypertension
smoking acutely elevates BP but has not been causally linked to hypertension
stop though bc both smoking and hypertension are risk factors for CVD
alcohol and hypertension
excessive alcohol consumption elevates BP
it can also decrease the response to some antihypertensive meds
3 types of diuretics and where they work
diuretics block Na and Cl ion reabsorption in the nephron of the kidney and therefore prevent reabsorption of water = decreased CO and decreased BP
loop diuretics - thick ascending limb of loop of Henle (most effective)
thiazide diuretics - distal tubule (medium effective)
K sparing/aldosterone antagonists - collecting duct (least effective)
loop diuretics
most effective
thick ascending limb of loop of henle
reserved for situations that need rapid fluid loss
edema
severe hypertension that doesn’t respond to the diuretics
sever renal failure
adverse effects of loop diuretics
hypokalemia (can cause fatal dysrhythmias)
hyponatremia
dehydration
hypotension
thiazide diuretics
most commonly used for hypertension
block Na and Cl reabsorption in the distal tubule and decrease vascular resistance
max amount of diuresis is much less than loop diuretics
often alone thiazide diuretics can control hypertension
K sparing diuretics/aldosterone antagonists
minimal lowering of BP
inhibit aldosterone receptors in the collecting duct, causing increased sodium excretion and potassium retention
usually in combination with loop or thiazide
don’t use with ACEIs
thiazide diuretic adverse effects
hypokalemia
hyponatremia
dehydration
K sparing adverse effects
hyperkalemia
how do beta blockers work
block cardiac beta 1 receptors
-> binding of catecholamines to cardiac beta receptors causes increased CO (so blocking decreases)
block juxtaglomerular beta 1 receptors
-> binding releases renin which activates RAAS causing vasoconstriction (blocking decreases PR)
are antagonists
olol suffix
beta blockers
ie propanolol
classes of beta blockers
1st generation
non-selective, block beta 1 in heart and juxtaglomerular and beta 2 in the lung
2nd generation
only block beta 1
beta blocker adverse effects
2nd gen: bradycardia (slow HR) decreased CO heart failure rebound hypertension if stopped quickly (taper over 10-14 days)
1st gen:
same as 2nd plus
bronchoconstriction (bad for ppl with asthma or pulmonary diseases)
inhibition of hepatic and muscle glycogenolysis (bad in diabetics if accidentally take too much insulin)
how do ACEIs work
decrease production of angiotensin II
-> decreasing it causes vasodilation (bc its a vasoconstrictor)
-> decreasing it also decreases total blood volume
ie decrease CO and PR
also inhibit the breakdown of bradykinin
-> elevated bradykinin causes vasodilation
so get decreased angiotensin II and increased bradykinin
pril suffix
ACEIs
ie captopril
adverse effects of ACEIs
generally well-tolerated
effects due to decrease angiotensin II
- 1st dose hypotension (first few should be low)
- hyperkalemia (bc of decreased aldosterone release)
- *don’t give K supplements or K sparing diuretics**
effects due to increased bradykinin
- persistent cough
- angioedema
Note: use with certain NSAIDs will decrease the effectiveness of ACEIs
how do angiotensin receptor blockers (ARBs) work
block binding of angiotensin II to AT1 receptors (vascular smooth muscle)
therefore cause vasodilation
also cause decreased aldosterone release from the adrenal cortex = increased sodium and water retention
sartan suffix
ARBs
ie losartan
adverse effects of ARBs
don’t give cough like ACEIs bc they don’t affect bradykinin
do not cause hyperkalemia
also have lower incidence of angioedema than ACEIs
how do direct renin inhibitors (DRIs) work
bind renin and block the conversion of angiotensinogen to angiotensin I rate-limiting step
decrease plasma renin a lot, but the BP lowering effects are about the same as ARBs and ACEIs
adverse effects of DRIs
hyperkalemia
don’t use with ACEIs, K sparing diuretics etc
very low incidence of persistent cough and angioedema
diarrhea
how do claim channel blockers (CCBs) work
block the entry of Ca into heart cells and smooth muscle cells, which decreases contraction
types of CCBs
dihydropyridine CCBs
non-dihydropyridine CCBs
dihydropyridine CCBs
significantly reduce Ca influx into smooth muscle of arteries
causes vasodilation
at therapeutic doses DO NOT act on the heart
dipine suffix
dihydropyridine CCBs
non-dihydropyridine CCBs
block Ca influx in both the heart and arterial smooth muscle
vasodilation and decreased CO
adverse effects of dihydropyridine CCBs
flushing dizziness headache peripheral edema reflex tachycardia rash
adverse effects of non-dihydopyridine CCBs
constipation dizziness flushing headache edema may compromise cardiac function **be careful if using in patients with heart failure**
centrally-acting alpha 2 agonists
bind to and activate alpha 2 receptors in the brainstem
decreases SNS output to heart and blood vessels
get decreased CO and PR (SNS normally causes increased CO and vasoconstriction)
adverse effects of centrally-acting alpha 2 agonists
drowsiness
dry mouth
rebound hypertension if withdrawn abruptly
treatment for prehypertension only
lifestyle
if not then thiazide diuretic
treatment for stage 1 hypertension only
lifestyle
then thiazide diuretic
if not then thiazide diuretic + ACEI, ARB, BB or CCB
treatment for stage 2 hypertension only
lifestyle + thiazide + ACEI, ARB, BB or CCB
treatment for hypertension with moderate renal disease or diabetes
lifestyle + thiazide + ACEI or ARB
treatment for hypertension with severe renal disease
lifestyle + loop + ACEI or ARB
neuropharmacology
study of how drugs affect the CNS
treat the symptoms not the cause rn
resting cell membrane potential
-70 mV
signal transmission at synapse
action potential reaches pre-synaptic nerve terminal, causes influx of Ca
Ca influx causes vesicles containing neurotransmitters to fuse and release contents
neurotransmitters bind to receptors on post-synaptic nerve terminal
monoamines
norepinephrine - depression and anxiety
epinephrine - anxiety
dopamine - parkinson’s and schizophrenia
serotonin - depression and anxiety
amino acids
excitatory - glutamate and aspartate (Alzheimer’s)
inhibitory - GABA and glycine (anxiety)
other neurotransmitter
acetylcholine - Alzeheimer’s and Parkinson’s
basic mechanisms for CNS drug therapy
replacement - NTs that are low
agonist/antagonist - bind to receptors on post-synaptic membrane
inhibiting breakdown - more NT
blocking reuptake - more NT in synapse
nerve stimulation - directly stimulate nerve to release more NT
what happens to the brain in parkinson’s
progressive loss of dopaminergic neurons in the substantia nigra (more than with normal aging)
symptoms of parkinson’s
tremor (especially extremities i.e. hands, arms, legs, jaw)
rigidity (join stiffness and increased muscle tone)
bradykinesia (especially slow to initiate movements)
masklike face (can’t show facial expression, difficulty blinking, swallowing)
postural instability (difficulty balancing while walking)
dementia (later in disease)
pathophysiology of parkinson’s
imbalance between acetylcholine and dopamine in the brain, causes increased BAGA release
decreased dopamine = not enough dopamine to inhibit GABA release
excess acetylcholine = increased GABA release
excess GABA (inhibitory NT) causes the movement disorders seen in PD
aetiology of PD
largely idiopathic
drugs - MPTP causes irreversible death of dopaminergic neurons (byproduct of illicit street drug synthesis)
genetics - mutations in alpha synuclein, parkin, UCHL1 and DJ-1 predispose
environmental toxins - some pesticides
brain trauma - increased risk
oxidative stress - ROS are known to cause degeneration of dopaminergic neurones **link between diabetes induced oxidative damage and PD
2 strategies for treating PD
increasing dopamine
decreasing acetylcholine
5 agents for increasing dopamine in PD
dopamine replacement dopamine agonist dopamine releaser catecholamine-o-methyltransferase inhibitor monoamine oxidase-B inhibitor
how does L-DOPA work
dopamine replacement
most effective drug for PD
however, beneficial effects decrease over time as disease progresses
crosses the BBB by active transport is a prodrug that is converted to dopamine in dopaminergic nerve terminals by decarboxylases in he brain vitamin B6 (pyridoxine) speeds up this reaction
why L-DOPA instead of dopamine
dopamine won’t cross BBB
dopamine has a very short half life in blood
L-DOPA adverse effects
nausea and vomiting - due to dopamine-mediated activation of the chemoreceptor trigger zone in the medulla
dyskinesias (abnormal involuntary movements)
cardiac dysrhythmias - conversion of L-DOPA to dopamine in the periphery can activate cardiac 1 beta receptors
orthostatic hypotension (when you stand up)
psychosis (hallucinatoins, vivid dreams/nightmares, paranoid thoughts)
L-DOPA peripheral metabolism and how we combat this
very little L-DOPA reaches the brain
the rest is metabolized in peripheral tissue, mostly the intestine
for this reason L-DOPA is usually given with carbidopa, a decarboxylase inhibitor
this allows a lot more to reach the brain, so you can lower the dose which will decrease the incidence of cardiac dysrhythmias and nausea and vomiting
2 types of loss of effect of L-DOPA
wearing off - gradual
on-off - abrupt
wearing off of L-DOPA
gradual
normally at the end of the dosing interval, indicates that drug levels may be low
minimized by:
- shortening dosing interval
- giving a drug that inhibits L-DOPA metabolism (i.e. a COMT inhibitor)
- add a dopamine agonist to therapy
on-off on L-DOPA
abrupt
can occur even when drug levels are high
minimized by:
- dividing medication into more doses per day
- using a controlled release formulation
- moving protein-containing meals to the evening
how do dopamine agonists work for PD
directly activate dopamine receptors on the post-synaptic cell membrane
not as effective as L-DOPA
first line treatment for PD patients with milder symptoms
dopamine agonist adverse effects
hallucinations
daytime drowsiness
orthostatic hypertension
how do dopamine releasers work for PD
stimulate release of dopamine from dopaminergic neurons AND block dopamine repute into pre-synaptic nerve terminals
AND block NMDA receptors
response is rapid, 2-3 days
not as effective as L-DOPA, given in combination with it or alone for milder symptoms
blockade of NMDA receptors is thought to decrease dyskinesia side effect of L-DOPA
dopamine releaser side effects
dizziness nausea vomiting lethargy anticholinergic side effects (i.e. dry mouth, hallucinations, sedation)
how do catecholamine-o-methyltrasferase inhibitors (COMTs) work for PD
COMT adds methyl groups to both dopamine and L-DOPA to inactivate them
inhibit COMT = greater fraction of L-DOPA that is available to be converted to dopamine
only moderately effective for PD, often given in combination with L-DOPA
adverse effects of COMTs
similar to L-DOPA
nausea
orthostatic hypotension
vivid dreams and hallucinations
how do monoamine oxidase- B (MAO-B) inhibitors works for PD
MAO-B metabolizes dopamine and L-DOPA by oxidizing them, inactivates them
is in both the brain and periphery
inhibit oxidation, more L-DOPA can be converted to dopamine in the brain
inhibition of dopamine metabolism allows more dopamine to remain in nerve terminals and be released
only moderately effective, usually given with L-DOPA
at therapeutic doses does not inhibit MAO-A in the liver, so won’t cause hypertensive crisis with tyramine
what does excessive acetylcholine do in PD?
causes diaphoresis (excess sweating), salivation and urinary incontinence
how do anticholinergic drugs work for PD
are antagonists, block the binding of acetylcholine to its receptor
may increase the effectiveness of L-DOPA
decrease the incidence of diaphoresis, salivation and incontinence
usually only for younger patients
adverse effects of anticholinergic drugs
dry mouth blurry vision urinary retention constipation tachycardia
elderly patients may experience sever CNS side effects i.e. hallucinations, confusion and delirium, so usually only give to younger patients
is Alzheimer’s more common in men or women
women
symptoms of Alzheimer’s
memory loss
problems with language, judgement, behaviour and intelligence
early symptoms - confusion, memory loss and difficulty with conducting routine tasks
later on problems with eating, bathing, speaking, controlling bladder and bowel function
pathophysiology of Alzheimer’s
degeneration of cholinergic neurons in the hippocampus early in disease
degeneration of neurons in the cerebral cortex later
linked to decreased cholinergic nerve function (have very little function)
have enlarged ventricles and a decreased brain size
how to diagnose Alzheimer’s
cannot do until after death and sample brain
hallmarks are neurofibrillary tangles and neuritic plaques
neurofibrillary tangles
form inside neurons when MT arrangement is disrupted
cause is abnormal production of tau, a protein that is responsible for forming cross bridges between MTs to keep their structure
neuritic plaques
outside of neurons
made mainly of beta amyloid
beta amyloid has been shown to kill hippocampal cells and causes Alzheimer’s like symptoms when injected into monkeys
aetiology of Alzheimer’s
mostly unknown
some cases are genetic i.e. DNA mutations
people with 2 copies of ApoE4 are at increased risk - ApE4 promotes formation of neuritic plaques by binding to beta amyloid
also increased incidence in people with mutations in the amyloid precursor gene
head injury is also a risk factor
is drug treatment of Alzheimer’s effective?
no shows only minimal improvement in the symptoms
classes of drugs for treatment of Alzheimer’s
cholinesterase inhibitors
NMDA receptor antagonists
cholinesterase inhibitors of Alzheimer’s
inhibit acetylcholinesterase from metabolizing acetylcholine
more acetylcholine stays in the synaptic cleft
can only enhance cholinergic neurotransmission in the remaining healthy neurons
minimal benefit on some measures of memory
only effective in a small proportion of patients
adverse effects of cholinesterase inhibitors
nausea and vomiting
diarrhea
insommnia
NMDA receptor antagonists for Alzheimer’s
NMDA is a Ca channel that is normally blocked by magnesium, when glutamate binds, Mg dissociates and Ca can enter the post-synaptic neutron
normal Ca influx is needed for learning and memory
in Alzheimer’s there is excess glutamate release so the NMDA receptor remains open and excess Ca enters the cell
- > this is detrimental to learning and memory
- > causes degradation of neurons
so antagonists block the calcium influx so that the increased glutamate ant cause prolonged Ca influx
adverse effects of NMDA receptor antagonists
well tolerated
no significant adverse effects in clinical trials (i.e. none were more than placebo)
schizophrenia
makes it hard to tell the difference between real and unreal experiences, to think logically, to have normal emotional responses and to behave normally in social situations
do not have multiple personalities
are not usually violent
common mental disease, usually begins in adolescence or early adulthood
positive symptoms of schizophrenia
exaggerate or distort normal neurological function
delusions hallucinations agitation paranoia combativeness disorganized speech disorganized thinking
negative symptoms of schizophrenia
loss of normal neurological function
social withdrawal poverty of speech poor self care poor insight poor judgement emotional withdrawal blunted affect lack of motivation
etiology of schizophrenia
largely unknown
risk factors:
- family history, more likely if both parents have it
- drug abuse (crystal meth/methamphetamine, phencyclidine/PCP/angel dust, lysergic acid diethylamide/LSD) are all known to cause it
- low birth weight
- low IQ
basal ganglia in schizophrenia
involved in movement and emotions
in schizophrenia abnormal activity is thought to play a role in paranoia and hallucinations
frontal lobe in schizophrenia
involved in problem solving and insight
schizophrenia - difficulty planning actions and organizing thoughts
limbic system in schizophrenia
involved with emotions
schizophrenia - contributes to agitation
auditory system in schiozphrenia
overactivity contributes to hallucinations
occipital lobe in schizophrenia
processes visual info
schizophrenia - interpreting images, reading emotion on others faces and recognizing motion
hippocampus in schizophrenia
mediates learning and memory which are decreased in schizophrenia
pathophysiology of schizophrenia
thought of as a disorder with increased dopaminergic nerve transmission i.e. excess dopamine
drugs that block dopaminergic function decrease some of the positive symptoms
5-HT/serotonin also plays a role, there are decreased 5-HT2A receptors and increased 5-HT1A receptors in the frontal cortex
glutamate binds to and activates NMDA receptors, PCP is a strong antagonist of NMDA and causes many schizophrenia symptoms
patients with schizophrenia have decreased NMDA receptors in some regions of their brain
what receptors does dopamine bind to
D2
how is schizophrenia diagnosed
no definitive test
usually made by psychiatrist after interviewing the patient and family
look at changes in function of the patient, developmental background, family history, response to medication and brain scans
schizophrenics generally have enlarged ventricles and decreased frontal lobe activity
general stuff about schizophrenia drug treatment
want to block dopamine and/or serotonin neurotransmission in the brain
there are conventional and atypical antipsychotics
differ in their mechanism of action an side effect profiles
both are in use today
how do conventional antipsychotics work
act primarily by blocking the dopamine D2 receptors in the mesolimbic area of the brain
to a lesser degree also block acetylcholine, histamine and norepinephrine receptors
potency of them is directly proportional to their ability to inhibit D2 receptors
more effective at treating the positive symptoms
initial effect may be seen in 1-2 days but substantial improvement takes 2-4 weeks
adverse effects of conventional antipsychotics
extrapyramidal symptoms sudden high fever anticholinergic effects orthostatic hypotension sedation skin reactions
extrapyramidial symptoms
resemble symptoms of PD
acute dystonia - involuntary spasm of muscles in the face, tongue, neck or back - usually early in therapy
parkinsonism - bradykinesia, mask like faces, rigidity, stooped posture - can treat with an anticholinergic but L-DOPA must be avoided
akathesia - pacing, squirming, and a desire to continually be in motion - typically occurs early in treatment
tardive dyskinesia - in patients on long-term therapy, is irreversible so early detection is necessary, symptoms include involuntary twisting and writhing of face and tongue along with lip smacking - need to be switched to an atypical antipsychotic
atypical antipsychotics
block both dopamine D2 receptors and 5-HT1A and 5-HT2A receptors
affinity to D2 receptors is low, therapeutic action is attributed to blockade of 5-HTs
have the same efficacy against positive symptoms
much greater efficacy against negative symptoms
much lower risk of extrapyramidal symptoms, especially tariff dyskinesia (bc of decreased D2 receptor blocking)
adverse effects of atypical antipsychotics
sedation, anticholinergic effects and orthostatic hypertension (same as conventional)
weight gain (sometimes severe) risk of type II DM
what is epilepsy
neurological disorder that produces brief disturbances in the normal electrical activity in the brain
characterized by brief, sudden seizures (vary from person to person)
seizure
a sudden alteration of behaviour that is cause by CNS dysfunction
sudden and transient
epileptic seizure
a seizure that is caused by primary CNS dysfunction
due to excess depolarization and hypersynchronization of neurons
non-epileptic seizure
a seizure-like episode that is not the result of abnormal electrical activity in the brain
epilepsy
a tendency for recurrent spontaneous epileptic seizures
status epilepticus
a single unremitting epileptic seizure of duration longer than 30 min
OR
frequent seizures without recovery of awareness in between
is an emergency
focal/partial seizures
arise in one area of the brain
can be simple or complex
simple partial seizure
involve no loss of consciousness
symptoms depend on where the seizure activity is arising from
sudden, transient and brief
contralateral symptoms
complex partial seizure
loss of consciousness may appear to be awake but are not aware of surroundings symptoms depend where activity is contralateral no memory of events post-ictally brief
generalized seizure
bilateral, diffuse onset and seem to arise from all areas of the brain at once
5 types:
- absence
- tonic/clonic
- myoclonic
- tonic
- atonic
absence seizures
petit-mal
loss of consciousness
behavioural arrest
staring
brief, but may occur in clusters
rarely associated with automatism (unusual purposeless movements)
more common in childhood
tonic/clonic seizures
grand-mal
abrupt loss of consciousness
tonic period (muscles become rigid)
followed by clonic period (involuntary muscle contractions i.e. shaking)
may become incontinent and have tongue biting
post-octal may be drowsy, confused and frequently have headaches
myoclonic seizures
sudden, brief muscle contractions that can involve any muscle group
usually no loss of consciousness
sometimes associated with later development of generalized tonic/clonic seizures
tonic seizures
sudden muscle stiffening
impaired consciousness
atonic seizures
sudden loss of muscle tone
brief
“drop seizures”
secondary generalized seizure
begins in one area of the brain and then spreads to the rest
preliminary focal phase is sometimes called an “aura” - some ppl experience it and know they’re going to have a more serious seizure
how do you determine where a focal seizure is occurring
from the symptoms
frontal lobe focal seizure
simple repetitive motor movements involving a localized muscle group are associated with contralateral primary motor cortex
tonic posturing affecting the entire side of the body are associated with contralateral Supplemental Motor Area and other higher level motor structures
very complex behavioural automatism that involve bilateral movement i.e. bicycling are associated with higher areas of the frontal cortex - often also have laughter, vocalizations etc
temporal lobe focal seizure
emotions i.e. anger, fear, deja vu
auditory hallucinations of buzzing or voices, olfactory hallucinations
visual distortions, paresthesias and autonomic disturbances also hard to distinguish from parietal
parietal lobe focal seizure
localized parethesias i.e. numbers or pins and needles are associated with contralateral somatosensory cortex
more complex and widespread parethesias is associated with somatosensory association cortex
complex multi-sensory hallucinations and illusions can be higher order sensory association areas hard to distinguisj from temporal
occipital lobe focal seizure
visual hallucinations ie flashing or a repeated pattern in the environment (not usually objects or faces)
temporary blindness or decreased vision, sensation of eye movement, reflex nystagmus
can be mistaken for migraines
how is epilepsy classified
symptomatic epilepsy - arising from an identified cause i.e. brain tumour, stroke, infection, injury
idiopathic epilepsy - no identifiable cause, usually have family history and genetics are probably involved
cryptogenic epilepsy - likely to have an underlying cause that hasn’t been identified
seizure threshold
everyone has a seizure threshold and what it is affects how susceptible you are to seizures
affected by stroke, head injury, drug/alcohol withdrawal, infection, tutor, severe fever, visual stimuli (flashing lights)
4 ways anti epileptic drugs work
blocking Na channels
blocking voltage-dependent Ca channels
glutamate antagonists
potentiating the actions of GABA
blocking Na channels for epilepsy
blocking Na channels prolongs the inactivation state so that neurons can’t fire at a high frequency
phenytoin
most common anti-epileptic drug (AED)
blocks Na channels
useful for all seizures EXCEPT absence seizures
non-linear kinetics
narrow therapeutic range, often undergoes therapeutic drug monitoring
adverse effects of phenytoin
sedation
gingival hyperplasia
skin rash
teratogenic
blocking voltage-dependent Ca channels for epilepsy
inhibit Ca channels on presynaptic neuron so that neurotransmitter isn’t released
glutamate antagonists for epilepsy
glutamate is excitatory therefore block it and you will decrease CNS excitation
do this by either blocking the NMDA or AMPA channels (these are what glutamate binds to)
potentiating the actions of GABA for epilepsy
GABA is inhibitory, it binds to its receptor and causes CL to come into the cell, hyperpolarizing
potentiate GABA 4 ways:
- enhance binding of GABA to its receptor
- stimulate GABA release
- inhibit GABA reuptake
- inhibit GABA metabolism
which AEDs are traditional vs newer and what is the difference
phenytoin and valproic acid are traditional
lamotrigine is newer
effectiveness is similar between them, but newer tend to have fewer side effects and a decreased propensity to induce hepatic drug metabolizing enzymes (i.e. fewer drug-drug interactions)
diagnosis of depression
at least 5 for at least 2 consecutive weeks:
- depressed mood most of the day, nearly everyday
- loss of interest or pleasure in almost all activities
- significant weight loss or gain
- insommnia or hyperwsommnia
- psychomotor agitation or retardation
- fatigue and energy loss
- feelings of worthlessness or excessive guilt
- decreased ability to think, concentrate or excessive indecisiveness
- recurrent thoughts of death or suicide
exogenous depression
triggered by external stimuli
pathological grief
adjustment disorder
endogenous depression
may or may not be related to external events
major, severe, atypical depression dysthymia SAD postpartum bipolar
pathological grief
prolonged grieving with excessive guilt
psychotherapy more effective than drugs
adjustment disorder
prolonged depression following failure i.e. losing job
commonly have hyperwsommnia and hyperphagia
psychotherapy more effective than drugs
major depression
loss of interest and lack of response to positive stimuli
usually worse in the morning
insommia and weight loss
severe depression
major depression but added suicidal ideation and psychoses
atypical depression
major depression but have the atypical symptom of hyperwsommnia and hyperphagia
often obese
dysthymia
mood is regularly low but symptoms are not as severe as major depression
more noticeable to family/friends
psychotherapy better than drugs
SAD
mild or moderate symptoms of depression related to lack of sunlight
usually only in the winter
postpartum depressoin
moderate to severe depression after birth
usually within 3 months of delivery but may be up to a year after birth
biopolar disorder
alternating periods of elevated or irritable mood and periods of depression
monoamine hypothesis
suggests that altered monoamine release, receptor sensitivity or post-synaptic function lead to the symptoms of depression
mechanisms of antidepressants
inhibiting monoamine uptake
inhibiting monoamine metabolism
4 classes of antidepressants
tricyclic
selective serotonin reuptake inhibitors
selective serotonin/norepinephrine reuptake inhibitors
monoamine oxidase inhibitors
tricyclic antidepressants
3 ring structure
inhibit repute of serotonin and norepinephrine
effective for major depression
adverse effects of tricyclic antidepressants
antocholinergic effects sedation orthostatic hypotension decreased seizure threshold cardiac toxicity weight gain sexual dysfunction
SSRIs
only block serotonin reuptake
similar efficacy to TCAs, but lower incidence of side effects
most commonly used drugs for depression
usually used for major depression
SSRI adverse effects
weight gain
sexual dysfunction
insommnia
serotonin syndrome
serotonin syndrome
increased serotonin transmission can result in agitation, confusion, anxiety, hallucinations and incoordination
may appear within 3 days of initial therapy and stop when drug is stopped
SNRIs
block repute of both serotonin and norepinephrine
for major depression
faster onset of action
adverse effects of SNRIs
nausea
diastolic hypertension
sexual dysfunction
MAOIs
MAOs inactivate monoamines
MAO-A - serotonin and norepinephrine
MAO-B - dopamine
MAOIs inhibit both A and B
inhibit the metabolism go monoamines in the pre-synaptic neuron (i.e. there is more there that can be released)
useful for atypical depression and dysthymia
MAOI adverse effects
CNS excitiation - anxiety, insomnia, agitation
orthostatic hypertension
hypertensive crisis if you eat foods with tyramine
biopolar manic phase symptoms
irritation inflated self-esteem little need for sleep poor control of anger reckless behaviour (i.e. binge drinking, eating, drugs) easily distracted
pattern of bipolar disorder
no real pattern may have mostly one with the occasional other
on average have 2 episodes every 5 years
3 types of drugs to treat bipolar
mood stablizers
antipsychotics
antidepressants
mood stabilizers
relieve symptoms during manic or depressive episodes
prevent recurrence of manic or depressive episodes
do not worsen symptoms or alter rate of cycling
primary ones are lithium and valproic acid (AED)
how does lithium work
not understood but thought to alter the uptake and release of glutamate and block binding of serotonin
has narrow therapeutic range, and plasma [ ] can be altered by Na
agents that increase Na loss i.e. diuretics increase Li concentrations and may produce toxicity including GI upset, tremor, sedation and hypotension
antipsychotics for bipolar
acutely control symptoms during manic episodes and long term help stabilize mood
benefit patients even if they don’t have psychotic symptoms
atypical are preferred bc they have a lower risk of extrapyramidal symptoms
antidepressants for bipolar
treat depressive episodes
always combined with a mood stabilizer (so you don’t cause a manic episode)
no evidence for which antidepressant works best for bipolar
anxiety
normal physiological response
a disorder exists when the symptoms create a functional impairment
likely to also have depression
generalized anxiety disorder
overwhelmed with uncontrollable worrying
unrealistic or excessive worry about several activities that lasts 6 months or longer
panic disorder
sense of impending doom unrelated to stressors
panic attacks - sudden in onset, heart palpitations, chest pain, shortness of breath, dizziness
often confused for a heart attack
agoraphobia
patient feels judged or a situational anxiety where escaping would be difficult or embarrassing
OCD
persistent obsession and compulsions that interfere with daily life i.e. hand washing, checking locks
social anxiety disorder
anxiety in social situations
may not be able to talk or eat in front of others, use public washrooms
PTSD
anxiety that occurs after experiencing a traumatic events
re-experience the event and have severe insomnia
simple phobia
related to a specific fear i.e. spiders, elevators
classes of drugs for anxiety
benzodiazepines
buspirone
antidepressants
benzodiazepines
first line therapy for anxiety
potentiate the actions of GABA at the GABA receptor
are NOT GABA agonists, they bind to a different site and cause increased GABA binding
when GABA binds it causes chloride ions to move into the cell and causes CNS depression
amplify the actions of endogenous GABA so are limited in how much CNS depression they produce - therefore are safer than agonists i.e. barbiturates
used for anxiety, seizures, insomnia, alcohol withdrawal, muscle spasms
different dosages i.e. higher for insomnia than anxiety
effective for generalized anxiety disorder and social anxiety disorder
adverse effects of benzodiazepines
CNS depression - drowsiness, difficulty concentrating
anterograde amnesia - impairment of memory of events that occur following dosing
respiratory depression - especially if combined with alcohol
teratogenic
tolerance - only for seizures
withdrawal - need to taper off slowly
buspirone
not a CNS depressant, it appears to modulate serotonin/dopamine neurotransmission
useful in ppl who drink alcohol since it is not a CNS depressant
only effective for generalized anxiety disorder
no tolerance or physical dependence
effects are slow though, ineffective for immediate relief
well-tolerated, non-sedating
dizziness, lightheadedness and excitement
antidepressants for generalized anxiety disorder
SSRIs and SNRIs, but are slow like buspirone
antidepressants for panic disorder and agoraphobia
SSRIs, TCAs and MAOIs, but take 6-12 weeks to appear
SSRIs are preferred bc they are better tolerated
antidepressants for OCD
SSRIs are first line
also require behavioural therapy
antidepressants for social anxiety
SSRIs are first line, benzodiapenes may be used
benzodiazapenes provide immediate relief, SSRIs take longer
drug treatment for PTSD
there is none
classic symptoms of diabetes
polyuria, polyphagia, polydipsia and weight loss
what does insulin do
causes glucose uptake in the muscle, liver and fat cells
in liver make glycogen, decrease gluconeogenesis
in muscle use for energy and make protein, make glycogen
also causes uptake of AAs into muscle
in fat make fatty acids and TGs
how is extracellular K associated with insulin
it helps drive glucose into the cell
risk factors for T2DM
age exercise heart disease obesity native or african
diabetic retinopathy
most common cause of blindness in people under age 65
hyperglycemia damages retinal capillaries
tightly controlling blood sugar minimizes risk
should have eye exam once a year
diabetic nephropathy
proteinuria is the earliest sign
have decreased glomerular filtration and increased blood pressure
leading cause of morbidity and mortality it T1DM patients
tight control of blood glucose delays and reduces severity
ACEIs and ARBs are useful in preventing it, regardless of blood pressure T1DM should take
CVD and diabetes
CVD including heart attack and stroke are the #1 for mortality and morbidity in T2DM
atherosclerosis develops in diabetics earlier
CVD in diabetes results from a combination of hyperglycaemia and altered lipid metabolism
statins should be taken to reduce risk regardless of LDL levels
diabetic foot ulcers
most common cause of hospitalization for diabetics
half of all lower limb amputations
should have regular foot exams
other diabetic foot complications
nerve damage - can’t feel pain etc
decreased blood flow - can’t heal and fight infection
nerves tha control moisture can get damaged, can’t remain moist get dry and cracked skin
skin can become thick or thin
toes can become bent (hammer toes)
FPG
fast for 8 hours
> 7 mmol/L = diabetes
*preferred test
CPG
anytime
> 11.1 mmol/L and have polydipsia, polyuria, weight loss = diabetes
if this suggests diabetes usually do FPG to confirm
OGTT
used when the others can’t definitively diagnose
give 75 g oral glucose then measure blood glucose 2 hours later
> 11.1 mmol/L = diabetes
glycosylated hemoglobin
high glucose, get glycosylated HbA1C
poor diagnostic, but good for average over 2-3 months
i.e. can look at how well responding to therapy
< 7% is target
besides tight control of BG what is the goal of diabetes treatment?
keeping blood pressure low
proper lipid levels
maintaining kidney function
T1DM lifestyle modifications
maintain weight
split food throughout the day every 4-5 hours
exercise because this increases the response to insulin and increases glucose tolerance
need to be careful about strenuous exercise
take insulin
measure BG 3+ times a day
T2DM lifestyle modifications
caloric restriction will often normalize insulin release and decrease insulin resistance
weight loss bc usually obese
exercise to stimulate glucose uptake
is insulin anabolic or catabolic
anabolic
promotes energy storage and conservation
catabolic effects of insulin deficiency
glycogenolysis
gluconeogenesis
decreased glucose utilization
all raise BG
short duration rapid acting insulin
insulin lispro
insulin aspart
insulni glulisine
with meal for post-prandial rise in glucose
subcutaneous, can be IV if necessary
all are clear solution
short duration slower acting insulin
unmodified human insulin
injected before meals to control post-prandial rises or infused to provide basal control of BG
subcutaneous or IM (rare)
following subcutaneous injection the molecules form small aggregates which slows the absorption
clear solution
intermediate duration insulin
neutral protamine hormone (NPH) insulin
insulin detemir
onset is delayed so not used for meals
injected once or twice daily to control BG between meals and in the evening
both are subcutaneous
NPH is cloudy suspension
insulin detemir is clear solution
why does NPH insulin have delayed action?
conjugated to a large protein called protamine, makes it less soluble and decreases absorption
why does insulin deter have delayed action?
molecules bind to each other which delays absorption
long acting insulin
insulin glargine
SC injection at bedtime once daily
long duration of action bc it has a low solubility at physiological pH
when injected it from micro precipitates that slowly dissolve and so its releases in small amounts over time
clear solution
mixing insulins
so that you only have to take one injection
only NPH insulin can be mixed with short acting ones
short acting should be drawn into syringe first
mixtures are stable
complications of insulin therapy
hypoglycemia
overdose causing rapid decrease in BG will activate SNS and cause tachycardia, palpitations, sweating, nervousness
more gradual CNS symptoms ie headache, confusion, drowsiness, fatigue occur
v severe can get coma, convulsions, death
managing hypoglycemia
needs to be treated rapidly to prevent irreversible brain damage
conscious, give fast acting oral glucose i.e. tablets, juice, honey
unconscious IV glucose may be required
keep glucagon just in case
oral glucose is preferred, then IV glucose then glucagon, but depends on the situation
give oral glucose when patient regains consciousness
glucagon won’t work in malnourished or starving patients (no glycogen)
classes of oral anti diabetic drugs for T2DM
biguanides sulfonylureas meglitinides thiazolidinediones (glitazones) alpha-glucosidase inhibitors gliptins
biguanides
usually the drug of choice for T2DM
increase sensitivity and number of insulin receptors
decreases hepatic gluconeogenesis
reduces intestinal glucose absorption
don’t increase insulin levels so no risk of hypoglycaemia
adverse effects of biguanides
nausea decreased appetite diarrhea decreased absorption of vitamin B12 and folic acid lactic acidosis (rare but serious) **no hypoglycemia**
sulfonylureas
stimulate insulin release from pancreas
also inhibit glycogenolysis
1st and 2nd generation
2nd are more potent and cause fewer drug interactions
adverse effects of sulfonylureas
hypoglycemia
prolonged use may cause pancreatic burnout
meglitinides
same mechanism as sulfonureas i.e. stimulate insulin release from the pancreas
shorter half life though so they are effective for postprandial
less likely to cause hypoglycemia
less likely to cause pancreatic burnout
thiazolidinediones (guitarrones)
increase insulin sensitivity and decrease hepatic gluconeogenesis
activate PPARgaama (intracellular receptor)
turns on genes that regulate carb metabolism
get increased GLUT transporters and therefore increased insulin sensitivity
also increase HDL and decrease TGs via activation of PPARalpha
adverse effects of glitazones
fluid retention/edema (shouldn’t use in heart failure)
headache
myalgia (muscle pain)
alpha glucosidase inhibitors
delay carb absorption in the intestine by blocking alpha glycosides from metabolizing them
reduces post-prandial rise in glucose
adverse effects of alpha glucosidase inhibitors
poorly absorbed, so its just intestine
flatulence cramps abdominal distention diarrhea decreased iron absorption
gliptins
inhibit dipeptidyl peptidase 4 (DPP-4) which breaks down the uncertain hormones GLP-1 and GIP
GLP-1 and GIP are released from the GI tract after a meal and cause increased release of insulin and decreased release of glucagon
inhibit DPP-4, have more GLP-1 and GIP to reach pancreas = more insulin and less glucagon
no known major adverse effects
incretin mimetics
synthetic uncertain analogs that mimic the actions on incretins
cause increased insulin release and decreased glucagon release
given by subcutaneous injection
used along with biguanides or sulfonylureas
adverse effects of uncertain mimetic
hypoglycemia
pancreatitis
virulence factors for bacteria
fimbriae and pilli
flagella
secretion of toxins and enzymes
invasion
fimbriae and pilli
hair-like structures that project from the surface of bacterial cells
allow bacteria to attach to certain sites in the body so they aren’t washed away
flagella
bacteria live in aqueous environments and need to be able to move to survive
flagella allow them to “swim” to the sites where they may survive
toxins and enzymes
some bacteria secrete toxins and enzymes
secreted toxins can cause nausea, vomiting, diarrhea, cramps, pain, fever, paralysis
toxins produced outside our body can mediate toxic reactions if they gain entry i.e. food poisoning
enzymes released can degrade tissue or breakdown Abs
invasion
some bacteria can enter our cells
gram staining
gram positive = purple because they have a thick peptidoglycan
gram negative = pink, thin peptidoglycan
gram positive vs gram negative
gram positive
thick peptidoglycan
techoic acids (rigidity, major surface antigen)
have surface proteins
gram negative
thin peptidoglycan
lipopolysaccharides (LPS, structural, major surface antigen)
outer membrane that protects from bile salts and detergents
have porins
note: peptidoglycan = cell wall
signs of infection
fever, malaise, local redness, swelling
increased respiratory rate and tachycardia
some patients won’t have a fever i.e. newborns (immature hypothalamus) or elder (decreased hypothalamic function)
other location-specific signs
selective toxicity
destroy bacteria instead of harming the host
- > disrupt bacterial cell wall
- > targeting enzymes that are unique to bacteria
- > disrupting bacterial protein synthesis
identifying bacteria
gram stain for structural features
culturing to properly identify is best
sometimes can’t i.e. ear infections, hard to get cultures
bacteriostatic
stop the growth and replication and then the immune system takes care of them
bactericidal
kill the bacteria
MIC
minimum inhibitory concentration
MBC
minimum bactericidal concentration
usually higher than MIC
infections that are hard to get to
meningitis UTI osteomyelitis abscesses otitis media
meningitis
meninges, cover the brain and spinal cord
bacterial is worse than viral
need to find antibiotic that will penetrate meninges
UTIs
any part of urinary system, bladder most common, often during catheterization
need antibiotic that will get to the urinary system in its active form
osteomyelitis
infection of the bone
few antibiotics will penetrate bone
abscesses
pus and other injected material collect under the skin
hard to treat bc they don’t have a blood supply
otitis media
infection of the middle ear
more common in children
hard to get antibiotics to the inner ear
how does immunological state of a patient affect antibiotic selection
can only use bactericidal in immune compromised ppl
i.e. people who have AIDS, organ transplant, cancer chemotherapy and the elderly
what is antibiotic resistance
when bacteria did respond to an antibiotic and have lost sensitivity over time
how do bacteria reduce drug at the site of the target to develop resistance
decrease uptake of drug or increase the expression of efflux pumps
how do bacteria increase drug inactivation
evolve to produce increased amounts of enzymes that inactivate antibiotics i.e. beta lactase that degrades all antibiotics with beta lactic ring
how do bacteria alter targets to acquire resistance
evolve mutations in the target i.e. mutate ribosome so antibiotic is ineffective at binding it
how to prevent antibiotic resistance
prevent infection (vaccinate etc)
diagnose and treat effectively
use antibiotics wisely
prevent transmission
antibiotic allergy
most commonly penicillin
can be anaphylactic urticaria (hives) anxiety swelling of hands, feet, throat difficulty breathing hypotension
usually within 20 min so monitor
most reaction sie vomiting, diarrhea and non-specific rash are not true allergic reactions
if having an allergic reaction stop antibiotic and monitor vital signs
may need to give diphenhydramine (antihistamine) or an epipen
serum sickness
takes 1-3 weeks to develop after antibiotic exposure
immune system improperly identifies drug or drug-protein complexes as harmful
get inflammation, fever, hives, rash, joint pain, itching, angioedema, enlarged lymph nodes
treat with antihistamine for itch, analgesics for pain and corticosteroids for inflammation
(plus stop the drug)
superinfection
special type of resistance
new infection that develops during the course of antibiotic therapy
broad spectrum ABs kill good and bad bacteria, destruction of normal flora can allow new bacteria to flourish
superinfection are caused by drug resistant bacteria so they are difficult to treat
how can destruction of normal flora affect you other than superinfection
intestinal bacteria synthesize vitamin K, need it if you are taking anticoagulant warfarin or have increased risk of bleeding side effects
intestinal bacteria also contribute to first pass metabolism, can get increased blood drug levels and toxicity
also involved in enterohepatic recycling, get decreased recycling, drug won’t be as effective i.e. contraceptives
bone marrow toxicity
rare but serious complication of AB therapy
aplastic anemia
thromocytopenia
agranulocytosis
leukopenia
teach patients to look for sore throat, bruising, fatigue
transpeptidases
form cross bridges between peptidoglycan strands to make the cell wall strong
autolysins
degrade peptidoglycan cell wall
penicillin binding proteins (PBPs)
transpeptidases and autolysins
how do penicillins work
inhibit transpeptidases and activate autolysis
disrupt cell wall synthesis and promote cell wall destruction
bacteria take up water and die
bactericidal
only effective against bacteria that are actively growing and dividing
more effective against gram positive because they don’t have an outer membrane
penicillin resistance
inability to reach target
inactivation
mutation in PBPs
predominantly done through inactivation using beta lactamases
(we now have beta lactase inhibitors)
narrow spectrum penicillins
gram positive
need to be IV or IM bc they get destroyed by gastric acid
pneumonia and meningitis
generally considered safe, allergy is the primary adverse effect
narrow spectrum penicillinase resistant penicillins
altered side chain so they aren’t susceptible to beta lactamases
gram positive
Staphylococci
less effective vs non-penicillinase producing bacteria
not effective for abscesses or bone
some are resistant MRSA
broad spectrum penicillins
gram positiv and negative
able to penetrate outer membrane of gram negative
readily inactivated by beta lactamases
extended spectrum penicillins
gram negative and positive
also effective against Pseudomonas aeruginosa, which is resistant to all other penicillins
susceptible to degradation by beta lactamases
cephalosporins
inhibit transpeptidases and activate autolysis (like penicillins)
bactericidal
1st, 2nd, 3rd, 4th generations
each one increases activity against gram negative, resistance to destruction by beta lactamases and ability to penetrate cerebrospinal fluid
allergy is most common adverse effect
suitable for ppl with penicillin allergy
vancomycin
potentially toxic drug used only for serious infections caused by MRSA including osteomyelitis, meningitis, pneumonia septicaemia
inhibits cell wall synthesis by binding to precursors of cell wall synthesis and blocking transglycosylation step in making cross bridges
may cause ototoxicity
rapid infusion may cause red person syndrome - flushing, rash, itching, hypotension
tetracyclines
protein synthesis inhibitors
bind to ribosome
broad spectrum
bacteriostatic
adverse effects
GI irritation
photosensitivty (stay out of UV and wear sunscreen)
susceptibility to superinfection
macrolide antibiotics
protein synthesis inhibitors
bind to ribosome
broad spectrum
bacteriostatic
GI upset
QT interval prolongation
oxazolidinones
protein synthesis inhibitors
bind to ribosome
narrow spectrum - gram positive only
bacteriostatic
effective in treating MRSA and vancomycin resistant enterococci so only used for these 2
may cause reversible myelosupression
aminoglycosides
protein synthesis inhibitors
bind to ribosome
narrow spectrum - gram negative only
bactericidal
rapidly lethal to bacteria
cause irreversible ototoxicity and reversible nephrotoxicity
sulfonamides and trimethoprim
given together
inhibit different stages of folic acid synthesis in bacteria
bactericidal
used for UTIs
sulfonamides inhibit diphydropteroate synthase
trimerthoprim inhibits dihydrofolate reductase
primary adverse effect is hypersensitivity reactions i.e. fever and photosensitivity
small risk of severe hypersensitivity reaction called Stevens-Johnson Syndrome
fluoroquinolones
inhibit DNA replication by inhibitings DNA gyros and topoisomerase IV
bactericidal
broad spectrum
adverse effects = GI symptoms i.e. nausea, vomiting, diarrhea
isoniazid
drug NAME, not class primary treatment for tuberculosis
inhibits mycelia acid synthesis, a component unique to the cell wall of bacteria that cause tuberculosis
only works for M tuberculosis
adverse effects = peripheral neuropathy and hepatotoxicity
top cancers men
prostate, lung, colon, rectum
top cancers women
breast, lung, colon, rectum
neoplastic
abnormal and uncontrollable cell growth
characteristics of cancer cells
persistent uncontrollable cell proliferation invasive metastatic immortal angiogenesis
treatment modalities for cancer
surger
radiation
chemotherapy
where does most toxicity to normal cells occur in chemotherapy
to cells with a high growth fraction
growth fraction is the ratio of proliferating to G0 cells
ie in bone marrow, GI epithelium, hair follicles, germinal epithelium of testes all have high growth fractions
do we have good tests to determine if 100% of cancer cells have been killed?
no
kinetics of chemotherapy
first-order
ie constant percentage at given dose
importance of early detection of cancer
almost always significantly progressed when diagnosed
better prognosis when treatment is started earlier
good way to do it is surgery and then chemo if possible
breast cancer screening
clinical exam
cervical cancer screening
pap smear
colorectal cancer screening
fecal occult blood test
high risk, colonoscopy
prostate cancer screening
digital rectal exam
prostate specific antigen blood test
skin cancer screening
self check for changes in skin marks/growths, sores that don’t heal properly
testicular cancer screening
self examination
how do solid tumors respond to chemotherapy
poorly because they have a large proportion of cells in the resting (G0) state (chemo drugs usually target proliferating cells)
mechanisms of resistance to chemotherapeutics
decreased uptake
increased efflux (P-glycoprotein)
decreased activation of prodrug (due to change in metabolizing enzymes)
reduced target sensitivity or increased cellular repair
decreased apoptosis
intermittent chemotherapy
trying to achieve max benefit
give intermittently to allow normal cells to recover, but kill cancer cells
only works if the normal cells grow back quicker than the cancer cells
why is combination chemotherapy useful
decreased resistance - won’t likely become resistance to all the drugs you’re using
increased cancer cell kill - different mechanisms can attack in different ways at the same time
decreased injury to normal cells - using drugs that don’t have overlapping toxicities can get greater anti-cancer effects safer than using one drug alone
common chemotherapeutic toxicities
bone marrow suppression
digestive tract injury
nausea and vomiting
bone marrow suppression
very high growth fraction
can result in neutropenia, thrombocytopenia, anemia
digestive tract injury during chemotherapy
stomatitis - inflammation of the oral mucosa
if severe can cause ulcer
diarrhea may occur secondary to damaging the lining - loss of electrolytes
nausea and vomiting in chemotherapy
give anti-emetic drugs, prevent dehydration and prevention malnutrition when this is occurring
types of cytotoxic anti-cancer agents
alkylating agents platinum compounds antimetabolites antitumor antibiotics mitotic inhibitors
cell-phase non-specific drugs
effective at any stage, however more effective in proliferating cells than G0 cells
alkylating agents
cell cycle phase non-specific
transfer an alkyl to N atoms on G residues in DNA and form crossbridges
get miscoding, breaking of DNA and possibly inhibition of DNA synthesis
cyclophosphamide
most common alkylating agent
prodrug, activated in the liver
therefore its onset of effect is often delayed
platinum compounds
cell cycle phase non-specific
contain platinum
cross-link DNA and inhibit DNA replication
bind to guanines similarly to alkylating agents
cisplatin
most common platinum compound
is extrememly nephrotoxic, ototoxic and emetogenic
antimetabolites
structurally similar to natural compounds the body uses for synthesizing cellular constituents or incorporating into DNA
inhibit particular enzymes to prevent DNA replication
phase-specific, most act during S-phase
1) folic acid analogs - block conversion of folate to its active form
2) purine analogs
3) pyrimidine analogs
antitumor antibiotics
kill cells by intercalating DNA
causes a change in structure of DNA, can’t be used as a template by DNAP
very poorly absorbed so are given IV
anthracyclines
type of antitumor antibiotic
effective and widely used
cause severe bone marrow suppression and are cardiotoxic
mitotic inhibitors
cell cycle phase specific
inhibit mitosis
vinca alkaloids and taxanes
vinca alkaloids
mitotic inhibitors derived from periwinkle plant blocks mitosis during metaphase binds to tubulin, major component of MTs disrupts organization of MTs and leads to inappropriate distribution of chromosomes and eventually cell death
taxanes
mitotic inhibitors
act in late G2, just before mitosis
stabilize MT bundles and prevent cell division
glucocorticoids for cancer
used in combination with other chemotherapeutic agents in cancers derived from lymphoid tissue
beneficial bc they are directly toxic to lymphoid tissue
side effects from long term use: osteoporosis, adrenal insufficiency, susceptibility to infection, GI ulceration, electrolyte disturbance and growth retardation
also helpful for complications of other chemo drugs including reduction in nausea, vomiting, pain and improved appetite
what is prostate tissue dependent on
androgens
how can androgen deprivation be achieved
gonadotropin releasing hormone agonist or surgically by castration
GnRH agonists cause transient increase in testosterone production in the testes (symptoms may worsen) but then cause decreased GnRH release through desensitization and negative feedback
net effect = less testosterone synthesis and release
can also use androgen receptor antagonists (block androgen receptors in cancer cells)
usually these 2 are given together
how is breast cancer treated
depriving breast cancer cells of estrogen
in combination with surgery and radiation
types of breast cancer drugs
anti-estrogens
aromatase inhibitors
trastuzumab
anti-estrogens
block estrogen receptors
tamoxifen is the most common one
is a partial agonist, minimally activates, but blocks endogenous estrogen for binding
aromatase inhibitors
aromatase converts androgens to estrogen
inhibit conversion = less estrogen available to breast cancer cells
do not block ovarian estrogen synthesis, so only are useful in post-menopausal women
trastuzumab
also called herceptin
monoclonal Ab that binds to HER2 receptors and prevents cell proliferation
(some cancers have increased HER2 receptors, they are especially aggressive tumors)
must be given IV bc it is an Ab
causes cardiotoxicity
tyrosine kinase inhibitors
imatinib is the prototype
is effective for chronic myelogenous leukaemia and gastrointestinal stromal tumours
causes complete inhibition of cellular proliferation and cause cell death via apoptosis
binds to bcr-abl fusion protein
primary toxicities are nausea, vomiting, edema, muscle cramps
