aging and disease lecture 7 & 8- drugs and aging

Question 1

what are physical changes related to?

Answer 1

normal aging and not diseases

Question 2

what happens as we age?

Answer 2

-change physically
-some systems slow down
-lifestyle changes can influence aging smoking, exercise, diet and alcohol use
-changes tend to be slight, often barely noticed and not problematic
-Steps can be taken to help prevent illness- often through use of drugs to maximise quality of life.
Drugs effects (and their side effects) can be influenced by age

Question 3

what are the 4 types of aging theories?

Answer 3

-wear and tears
-cellular theory (at birth there’s only a certain amount of usable cells)
-genetic mutation theory (the number of body cells exhibiting unusual or different characteristics increase with age)
-autoimmune theory (attributes aging to the decline of the body’s immunological system)

Question 4

what types of changes are cosmetic?

Answer 4

The skin wrinkles and sags
The dermal layer thins.
Less collagen is produced.
The elastin fibers that provide elasticity wear out.

Decrease in the function of sebaceous & sweat glands contributes to dry skin.
The fat cells get smaller- wrinkles become more noticeable and skin can sag.

Question 5

how does botox work?

Answer 5

1) after injection- binds to the surface of nerve cell
2) internalised into small vesicles in nerve
3) several proteins required for ach release. botox affects SNAP-25

Question 6

what happens to hair in aging?

Answer 6

-many men suffer from pattern baldness, causing increased hair growth in ears, nostrils and eyebrows. losing body hair elsewhere

Question 7

what does minoxidil do?

Answer 7

Opens KATP channels to hyperpolarise the membrane of vascular
smooth muscle cells- less sensitive to constriction

Not a first line drug for hypertension

Side-effect of hypertrichosis- bad for some patients- good for the
pharmaceutical/cosmetic industry!

Question 8

what changes occur in the valves?

Answer 8

• > thickness and < flexibility
• aortic and mitral valve calcification
• can lead to heart murmur
• long term hypertonic changes
• cam be treated by valve replacement

Question 8

what happens to the heart during aging?

Answer 8

Difficult to differentiate between age-related changes and those related to an inactive lifestyle or “abuse”

Are the changes normal ‘wear and tear’ or cardiovascular disease?

Question 9

how does the heart change anatomically?

Answer 9

• Thickening of the left ventricular wall
• > collagen, < elastin
• Heart becomes less efficient
• Supply of O2 to the body is reduced
• Fatigue, lower exercise tolerance

Question 10

what happens to the heart rate in aging?

Answer 10

• < cardiac responsiveness rate with exercise
• heart may take longer to return to baseline rate

Question 11

what happens to the changes in the conduction system?

Answer 11

• < number of pacemaker cells
• Fibrous tissue infiltration of conductive system
• Can lead to conduction abnormalities (arrhythmias)
• More prone to arrhythmias after an ischaemic event

Question 12

what are the norma SA node and intranodal atrial tract changes?

Answer 12

Irritability of the myocardium may result in extra systoles, along with sinus arrhythmias & sinus bradycardia

Question 13

what are the changes to heart contraction?

Answer 13

Excitation-contraction coupling is what makes the heart contract
Relies on the conducted impulse depolarising the membrane of the cardiac muscle cells (cardiomyocytes)
Calcium enters the cells and causes contraction
Rate and force of contraction can lower in the elderly- can lead to heart failure!

Question 14

what happens in heart failure and treatment due to aging?

Answer 14

Cardiac output falls- leading to fatigue, cyanosis, peripheral oedema, distensed jugular vein, pulmonary oedema.
Treatment is not curative- trying to either make the heart work harder to cope with demand or unload the heart in other ways such as:
-correcting hypertension
-blocking endogenous constrictor agents
-modulating return of blood to the heart

Question 15

what causes oedema in HF patients?

Answer 15

a fluid transport imbalance
Determined by Starlings Forces- hydrostatic pressure vs. osmotic pressure
Hydrostatic pressure forces fluid out at the arteriolar end and osmotic pressure draws fluid back in at the venous end.
Imbalance leads to net outward filtration = oedema.

Question 16

how do you prevent pulmonary oedema?

Answer 16

Pulmonary Hydrostatic pressures are
much lower than systemic pressure

Colloid pressure are equivalent

Therefore have a net fluid transfer at
both ends

Prevents pulmonary oedema

Question 17

what are heart failure drugs?

Answer 17

Nitrates- release a vasodilator called nitric oxide which dilates veins- lowers blood return to the heart and reduces workload.
Positive inotropic agents- block pumps in the cardiac muscle to increase calcium in the cells- heart contracts more strongly.
ACE inhibitors- inhibit an enzyme so body produces less AngII- blood pressure goes down and reduced water retention by kidney.

Question 18

what is normal blood pressure changes?

Answer 18

Systolic blood pressure may rise disproportionately higher than diastolic

Question 19

how do you determine the blood pressure in aging?

Answer 19

BP creeps up gradually with age. Related to structural changes in the arteries and especially with large artery stiffness.
Isolated systolic hypertension most common in patients over 50
Increases CV risk- MI, HF, stroke etc
Risk is predicted by pulse pressure = systolic – diastolic pressure

Question 20

what is the cause of hypertension?

Answer 20

Primary (Essential) hypertension (~90%) multifactorial:
-smoking
-obesity
-diet (e.g. salt)
-exercise (lack of)
-genetic

Secondary hypertension (<10 %)
e.g. renal hypertension or pheochromocytoma

Question 21

what are the changes in the blood vessels?

Answer 21

Large conduit arteries become stiffer, less elastic due to a reduction in elastin- normal aging
Can become calcified- bony
Stiffer vessels less able to accommodate systolic pulse of blood- get systolic hypertension
Calcified blood vessels also more difficult to dilate

Question 22

what changes occur to the coronary artery?

Answer 22

Supplies blood to the heart muscle via RCa, LCx and LAD
Coronary artery blood flow  between ages 20 & 60
Effect:  oxygen delivery to the heart muscle, thus  ability to increase activity
In extreme cases, narrowing leads to a condition known as angina
Angina is not a disease- it is pain due to cardiac ischaemia

Question 23

what changes occur to the aorta?

Answer 23

May become dilated, elongated, rigid
May develop calcifications and become tortuous
<Elastin, >collagen = calcification
Artery wall can weaken in specific area to cause aneurysm

= >stiffness, ,<compliance

Question 24

how do you treat high blood pressure?

Answer 24

Lifestyle changes
Drugs affecting the heart
-beta blockers
Centrally acting drugs
Hormone antagonists
-ACE inhibitors, ATII blockers
Drugs affecting the vessels
-alpha blockers
-nitrates
-calcium channel blockers
-K+ channel openers
-direct vasodilators
Drugs affecting circulating fluid volume
-diuretics

Question 25

what are beta blockers?

Answer 25

Late 1950s- Black notes that dichloroisoprenaline (DCI) can block the effects of adrenaline on the heart
Sees potential for a drug which protects the heart from adrenaline release during stress/emotion
Substitutes chlorine atoms on DCI to get first beta blocker- pronethalol
Quickly replaced by propranolol due to side effects in patients and animals
1988- Black awarded Nobel prize for development of beta blockers and anti-ulcer drugs

Question 26

what is propranalol?

Answer 26

Propranolol blocks Beta adrenoceptors on the heart- reducing force of contraction
and heart rate. Is used clinically for angina, hypertension, low doses for heart failure
And intention tremor.

Later Beta Blockers- selective for Beta 1 over Beta 2
eg Atenolol

Hydrophilic to prevent crossing blood brain barrier eg Celiprolol

Question 28

what is atherosclerosis? (inflammatory disease)

Answer 28

Affects the large and medium-sized arteries
Begins with appearance of fatty streaks early in life in aorta
Develops to raised lesions as uptake of lipid increases
Inflammatory cells present in the artery wall
Fibrous cap forms to protect lesion

Question 29

how do you treat atherosclerosis?

Answer 29

Drugs to lower lipid levels
Drugs to prevent platelets sticking to the fibrous cap
Drugs to lower BP
Drugs to prevent symptoms of coronary ischaemia (angina)

Question 29

how does CV link to other organs?

Answer 29

Changes in the cardiovascular system have direct effects on other organs

Question 30

what is metformin?

Answer 30

Metformin may alter metabolism of microbes in the gut. extend lifespan in E. coli and reduces lifespan when the microbe is resistant

Effects on metabolism

May contribute to side effects- gut upset.

ALSO USED IN TYPE 2 DIABETICS
MAY HAVE OTHER USES TOO!

Question 31

what is type 2 diabetes?

Answer 31

Over 400 people a day are diagnosed with diabetes in the UK alone (Diabetes UK)

Can be due to insufficient insulin production or insulin resistance-
often part of the metabolic syndrome. Results in HYPERGLYCAEMIA

Incidence: 30 million (1985), 135 million (1995), 217 million (2005)- estimated 392million people with type2 diabetes in 2015 (6% of the world’s population)

Type 2 now as common a diagnosis as type 1 in US teenagers

Women seem to be at a greater risk as well as South Asians, Pacific Islanders, Latin Americans and Native Americans- likely genetic basis

The five “hot spots”- India, China, United States, Indonesia and Japan

Who consider it a global epidemic.

Question 32

what are the differences between type 1 and 2 diabetes?

Answer 32

-type 1 = insufficient insulin
-type 2 = insulin resistance

Question 33

what are non-modifiable and modifiable risk factors for type 2 diabetes?

Answer 33

non-modifiable= age, race, genetics, family history
modifiable= high cholesterol, high bp, high weight, physical activity

Question 34

type 2 diabetes treatements?

Answer 34

Lifestyle changes- lose weight! Improve diet, take exercise and reduce alcohol- at least 3 months trial (BNF guidelines)

Sulphonylureas (glibenclamide, gliclazide)- stimulate pancreas to release more insulin. Side effect is hypoglycaemia, GI upset and occasional liver problems

SGLT-2 inhibitors and GLP-1 mimetics- Wygovy (Ozempic)

Question 35

what is metformin?

Answer 35

Metformin- activates AMPK- reduces hepatic glucose production, reduced intestinal absorption of glucose and increased local utilisation of glucose. Does not cause weight gain!

In 1918- Galega officinalis, a French lilac, was found to be high in guanidine and could reduce blood glucose (Bailey, 2017).
Has been used as a diabetes drug for more than 60 years- of main use in T2D (Bailey, 2017).
Many have other interesting effects and applications (Bailey, 2017).
It has been repurposed for various non-diabetic conditions due to its impact on cellular metabolism and aging pathways.

Question 36

what is metformin repurposing?

Answer 36

Alzheimer’s Disease
Metformin has potent anti-inflammatory properties, improves neuropathological changes linked to AD, and reduces cognitive decline in diabetics (Sharma et al., 2021).
Ischaemic Stroke
Metformin reduces cerebral infarct size and neuronal death in ischaemic rat models via activating the AMPK signalling (Sharma et al., 2021) .
Cancer
Anti-cancer properties of metformin have been linked to p53, an important tumour suppressor gene in human (Lv and Guo, 2020).
Metformin inhibits cell invasion and metastasis by activating AMPK and therefore inducing p53 phosphorylation (Lv and Guo, 2020).
By an AMPKindependent pathway, metformin inhibits growth of cancer cells by triggering apoptosis and autophagy (Lv and Guo, 2020).